Water → 6-(Chloromethyl)-N-[6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-2-pyridinecarboxamide

HRID 1615990Notes

Reaction equation

HRID 1615990 reaction equation
[Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=1.[NH:12]1[C:20]2[C:15](=[C:16]([C:21]3[CH:22]=[C:23]([NH2:39])[C:24]4[CH:25]=[N:26][N:27]([S:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)(=[O:32])=[O:31])[C:28]=4[CH:29]=3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.CCN(C(C)C)C(C)C.O>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:39][C:23]2[CH:22]=[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH:14]=[CH:13][NH:12]4)[CH:29]=[C:28]3[C:24]=2[CH:25]=[N:26][N:27]3[S:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])=[O:10])[CH:6]=[CH:5][CH:4]=1

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 582680186-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-amineHCID 866533026-(Chloromethyl)-2-pyridinecarbonyl chloride2×

Product 1

HCID 582679866-(Chloromethyl)-N-[6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-2-pyridinecarboxamide

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 6-(hydroxymethyl)-2-pyridinecarboxylic acid (500 mg, 3.27 mmol) in chloroform (10 ml) and N,N-dimethylformamide (DMF) (0.1 ml) was added thionyl chloride (1 ml, 13.70 mmol) and the mixture heated at 65° C. for 1 hr. Solvent was removed in vacuo and the residue was azeotroped with chloroform (5 ml) then dried on a high vacuum line for 30 mins to afford an orange oil (650 mg), presumed to be 6-(chloromethyl)-2-pyridinecarbonyl chloride. To solution of 6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-amine (1.37 g, 3.53 mmol) in chloroform (30 ml) at 0° C. was added DIPEA (1.232 ml, 7.05 mmol). Crude 6-(chloromethyl)-2-pyridinecarbonyl chloride (1.519 g, crude) in chloroform (15 ml) was added dropwise and the mixture was stirred at 0° C. for 15 min. Water (30 ml) was added and the mixture was extracted with DCM (50 ml), separating the layers by hydrophobic frit. The solvent was removed in vacuo and the residue was dissolved in DCM (5 ml) and added to the top of 2×100 g silica SPE cartridges. One cartridge was eluted with 0-100% EtOAc/cyclohexane over 60 mins on the FlashMaster II. Product-containing fractions were and concentrated. The resultant solid was dissolved in 1:1 DCM/MeOH and loaded onto a 20 g aminopropyl cartridge that had been pre-conditioned with MeOH. The cartridge was then eluted with 1:1 DCM/MeOH and the fraction obtained was blown down under a stream of nitrogen. The solvent was removed in vacuo to give the title compound as a pink solid (487 mg). The second cartridge was eluted with 0-100% EtOAc/DCM over 60 mins on the FlashMaster II. The product-containing fractions were combined and concentrated to give a further portion of the title compound as a pink solid (449 mg).

Workup

  1. extractionthe mixture was extracted with DCM (50 ml)
  2. customseparating the layers by hydrophobic frit
  3. customThe solvent was removed in vacuo
  4. dissolutionthe residue was dissolved in DCM (5 ml)
  5. additionadded to the top of 2×100 g silica SPE cartridges
  6. washOne cartridge was eluted with 0-100% EtOAc/cyclohexane over 60 mins on the FlashMaster II
  7. concentrationconcentrated
  8. dissolutionThe resultant solid was dissolved in 1:1 DCM/MeOH
  9. washThe cartridge was then eluted with 1:1 DCM/MeOH
  10. customthe fraction obtained
  11. customThe solvent was removed in vacuo

Sources & evidence

ORD record
ord-4cf49c23e3ce4047ac1a4827127fb274
Source dataset
uspto-grants-2014_07
Patent number
US08765743B2

Reaction notes

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